PB2276: MAHOGANY: A PHASE 3 TRIAL OF ZANUBRUTINIB PLUS ANTI-CD20 ANTIBODIES VS LENALIDOMIDE PLUS RITUXIMAB IN PATIENTS WITH RELAPSED OR REFRACTORY FOLLICULAR OR MARGINAL ZONE LYMPHOMA
Authors: Antonio Salar Silvestre, Judith Trotman, Clementine Sarkozy, Yuqin Song, Laurie H. Sehn, Loretta J. Nastoupil, Wanhua Zhang, Pierre Fustier, Richard Delarue, Pier Luigi Zinzani
Journal: HemaSphere (2023)

Topic: 18. Indolent and mantle-cell non-Hodgkin lymphoma - Clinical Background: Inhibition of Bruton tyrosine kinase (BTK) has emerged as a strategy for treatment of patients with B-cell malignancies including indolent non-Hodgkin lymphomas. Zanubrutinib is a second-generation, potent, and specific BTK inhibitor and has shown to be more effective and better tolerated than first-generation BTK inhibitors in several diseases including chronic lymphocytic leukemia/small lymphocytic lymphoma and Waldenström macroglobulinemia. Zanubrutinib is approved in >15 countries, including the United States and European Union, for patients with relapsed or refractory (R/R) marginal zone lymphoma (MZL) who received ≥1 anti-CD20-based regimen, based on the single-arm MAGNOLIA trial (Opat et al. Clin Cancer Res 2021). In R/R follicular lymphoma (FL), ROSEWOOD, a phase 2 randomized study of zanubrutinib plus obinutuzumab vs obinutuzumab, met its primary endpoint of increased overall response rate (ORR) at primary analysis (Zinzani et al. J Clin Oncol 2022). In this trial, zanubrutinib plus obinutuzumab in patients with R/R FL demonstrated deep and durable responses with a favorable safety profile. Aims: To compare the efficacy and safety of zanubrutinib plus an anti-CD20 monoclonal antibody vs lenalidomide plus rituximab in 2 independent cohorts, for patients with either R/R FL or MZL in MAHOGANY (BGB-3111-308, NCT05100862), a phase 3 randomized, open-label trial. Methods: Key eligibility criteria include histologically confirmed FL (grades 1-3A) or MZL, previously treated with ≥1 anti-CD20-based regimen, relapsed after or refractory to the most recent systemic therapy, in need of treatment, no prior BTK inhibitor exposure, and no prior resistance to a lenalidomide-based regimen. In the FL cohort, patients will be randomized 1:1 to zanubrutinib plus obinutuzumab (N=300) and lenalidomide plus rituximab (N=300). Randomization is stratified by age (≥60 years vs <60 years), number of prior lines of therapy (1-2 vs >2) and rituximab-refractory status (yes vs no). The primary endpoint is progression-free survival (PFS) assessed by an independent review committee (IRC), according to Lugano 2014 criteria. Key secondary endpoints are ORR by IRC assessment and overall survival. In the MZL cohort, patients will be randomized 1:1 to zanubrutinib plus rituximab (N=75) and lenalidomide plus rituximab (N=75). Randomization is stratified by age (≥60 years vs <60 years) and number of prior lines of therapy (1–2 vs >2). The primary endpoint is PFS assessed by IRC according to Lugano 2014 criteria. The key secondary endpoint is ORR by IRC assessment. Zanubrutinib is given at 160 mg twice daily or 320 mg once daily according to investigator, until progression or unacceptable toxicity. Obinutuzumab or rituximab are given for up to 8 infusions. Lenalidomide is given according to approved label for up to 12 cycles. Recruitment is ongoing. Results:Summary/Conclusion: Keywords: Follicular lymphoma, Non-Hodgkin’s lymphoma, Phase III, Marginal zone